The objectives of this project are to develop a novel prostate cancer model using hCYP1A mice and PhIP, to characterize the molecular changes of carcinogenesis, and to determine the prostate cancer preventive activity of a -tocopherol (-T) rich mixture of tocopherols (-TmT) which, unlike -T, is a more effective chemopreventive agent. The hypotheses are: 1) PhIP induces prostate carcinogenesis by causing mutagenic DNA-adduct formation accompanied by oxidative stress and inflammation, 2) a high-fat diet (HFD) can promote carcinogenesis, shortening the experimental period; and 3) -TmT can inhibit prostate carcinogenesis due to its antioxidant and anti-inflammatory actions as well as its inhibition of oncogenic signaling pathways. The specific aims are as follows: Aim 1. Develop the PhIP-induced prostate cancer model in hCYP1A mice and characterize the cellular/molecular changes involved. PhIP will be administered (200mg/kg, po) to male hCYP1A mice maintained on the AIN76A diet; then they will be kept either on AIN76A diet or the HFD (containing 20% fat). The development of prostate lesions and cancer will be monitored at 20, 30, 40, and 50 weeks. We will analyze the development of PIN and carcinoma in the prostate as well as determine the levels of cell proliferation (Ki67 and PCNA), apoptosis (cleaved caspase-3 and TUNEL), inflammation (NF-kB and CD45), and oxidative stress (8-OHdG and -H2AX), as well as the expression of GSTP1, E-cadherin, COX-2, p63, p27, Pten, Nkx3.1, p16, and Bcl-2 by immunohistochemistry (IHC). In the development of a faster model, we can also test the hypothesis that HFD promotes prostate carcinogenesis. The induction of prostate cancer by PhIP added to the diet will also be explored. Aim 2. Determine the prostate cancer preventive activity of tocopherols. The PhIP-treated hCYP1A mice will be put on the HFD or HFD supplemented with -TmT. -TmT is expected to decrease oxidative and nitrosative stress and inflammation as well as oncogenic signaling in the prostate, and prevents or delays the onset of PIN lesions and prostate carcinoma. Impact: This research will make an impact in prostate cancer research by 1) developing a novel and relevant model to study dietary factors and prostate cancer; 2) evaluating high fat diet as a risk factor; and 3) determining -TmT as a chemopreventive agent for prostate cancer.